This proposal seeks to implement a novel, systematic approach (developed during the past project period) to study the iontophoretic transport properties of human skin. The long term objective is to gain a basic and comprehensive understanding with the information to become a significant part of the fundamental data base to materially assist drug delivery scientists in the rational design of practical iontophoretic systems for trans- dermal drug delivery, especially for polypeptide drug delivery. The approach combines a rigorous theoretical framework (the modified Nernst- Planck theory) with judiciously designed experiments to factor out the various contributions to human skin iontophoresis. The effects of physical chemical factors such as the molecular size/configuration and charge of the permeant, the ionic strength and pH of the electrolyte solution, and the mode of iontophoresis (continuous D.C. versus pulsed D.C.) upon the iontophoretic flux of the permeant will be systematically investigated. The general question will be addressed: is polypeptide transport (both passive and iontophoretic) in accord with the modified Nernst-Planck theory? The phenomenon of field induced pore induction (electroporation) with the human epidermal membrane (HEM) will receive particular attention, and answers to the following questions will be sought. How do HEM permeability and pore size vary with amplitude and duration of the applied voltage? How do the relative contributions of the direct field effect and convective (electroosmotic) solvent flow vary with electroporation? Under what voltage regimens may alternating pulses or sinusoidal A.C. yield electroporation effects? The actions of chemical permeation enhancers operating via several different mechanisms will be systematically investigated, and the importance of the different mechanisms quantified. These enhancer situations will include (a) agents interacting directly with HEM to increase the effective pore size and/or the porosity/ tortuosity ratio, (b) enhancers influencing the rate, extent, and/or the threshold voltage of electroporation, and (c) agents influencing the direction and magnitude of electroosmosis. Finally, select studies will be conducted to assess the clinical relevance of important outcomes from the above in vitro HEM studies in an in vivo animal model (developed during the past project period).